Pharmaceutical aerosol formulation comprising a medicament, a propellant and a fluorinated surfactant

ABSTRACT

A pharmaceutical aerosol formulation which comprises particulate medicament, a fluorocarbon of hydrogen-containing chlorofluorocarbon propellant and a surfactant of general formula (I), wherein n is an integer of 1 to 18; m is an integer of 0 to 17; and R 1 , R 2  and R 3  are each independently a hydrogen atom or a C 1-4  alkyl group.

This application is filed pursuant to 35 U.S.C. §371 as a United StatesNational Phase Application of International Application No.PCT/IB95/00866, filed 27 Sep. 1995, which claims priority from 9419536.9(GB), filed 28 Sep. 1994.

This invention relates to aerosol formulations of use for theadministration of medicaments by inhalation.

The use of aerosols to administer medicaments has been known for severaldecades. Such aerosols generally comprise the medicament, one or morechlorofluorocarbon propellants and either a surfactant or a solvent,such as ethanol. The most commonly used aerosol propellants formedicaments have been propellant 11 (CCl₃ F) and/or propellant 114 (CF₂ClCF₂ Cl) with propellant 12 (CCl₂ F₂). However these propellants arenow believed to provoke the degradation of stratospheric ozone and thereis thus a need to provide aerosol formulations for medicaments whichemploy so called "ozone-friendly" propellants.

A class of propellants which are believed to have minimalozone-depleting effects in comparison to conventionalchlorofluorocarbons comprise fluorocarbons and hydrogen-containingchlorofluorocarbons, and a number of medicinal aerosol formulationsusing such propellant systems are disclosed in, for example, EP 0372777,WO91/04011, WO91/11173, WO91/11495 and WO91/14422. These applicationsare all concerned with the preparation of pressurised aerosols for theadministration of medicaments and seek to overcome the problemsassociated with the use of the new class of propellants, in particularthe problems of stability associated with the pharmaceuticalformulations prepared. The applications all propose the addition of oneor more of adjuvants such as alcohols, alkanes, dimethyl ether,surfactants (including fluorinated and non-fluorinated surfactants,carboxylic acids, polyethoxylates etc) and even conventionalchlorofluorocarbon propellants in small amounts intended to minimisepotential ozone damage.

It is well established in the art that fluorinated surfactants may beused to stabilise micronised drug suspensions in hydrofluorocarbonpropellants such as 1,1,1,2-tetrafluoroethane (P134a), see for exampleU.S. Pat. No. 5,126,123, WO91/11173, WO91/14422 and WO92/00062.Surprisingly, the applicants have now found that a particular group offluorinated surfactants may be used to prepare novel aerosolformulations, and can be advantageous in terms of reducing drugdeposition, increasing shelf life and like.

Thus, in one aspect the invention provides a pharmaceutical aerosolformulation which comprises particulate medicament, a fluorocarbon orhydrogen-containing chlorofluorocarbon propellant and a surfactant ofgeneral formula (Ia) or (Ib) ##STR2## wherein: R¹ represents:

R_(F) (CH₂)_(a) --(CH═CH)_(b) --(CH₂)_(c) --(CH═CH)_(d) --(CH₂)_(e)--A--;

R_(F) --(CH₂)_(f) --OCH₂ CH(CH₂ OH)CH₂ --A--;

R_(F) --(CH₂)_(g) --OCH₂ CH(CH₂ OH)--A--;

wherein --A-- represents --O--, --C(O)O--, --R⁶ (R⁷)N⁺ --, (wherein eachof R⁶ and R⁷ represents C₁ -C₄ alkyl or hydroxyethyl), --(CH₂)_(t) --,wherein t=0 or 1 or --C(O)N(R⁹)--(CH₂)_(q) --B, wherein q is an integerfrom 0 to 12, B represents --O-- or --C(O)--, and R⁹ is hydrogen or R⁶,

and wherein the sum of a+c+e is from 0 to 17, especially 0 to 11, thesum b+d is from 0 to 12 and each of f and g is from 1 to 12;

R_(F) --(CH₂ --CH₂ --O)_(h) --;

R_(F) --(CH(CH₃)CH₂ O)_(h) --;

R_(F) --(--CH₂ --CH₂ --S)_(h) --,

wherein h is from 1 to 12; and

wherein R_(F) represents a fluorine-containing moiety having one of thefollowing structures:

(a) F(CF₂)_(i) --, wherein i is from 1 to 18, especially 2 to 12

(b) (CF₃)₂ CF(CF₂)_(j) --, wherein j is from 0 to 8

(c) R_(F) 1(CF₂ CF(CF₃))_(k) --, wherein k is from 1 to 4, and R_(F) 1represents CF₃ --, C₂ F₅ -- or (CF₃)₂ CF--,

(d) R_(F) 2(R_(F) 3)CFO(CF₂ CF₂)_(l) wherein l is from 1 to 6 andwherein each of R_(F) 2 and R_(F) 3 independently represents CF₃ --, C₂F₅ --, n-C₃ F₇ -- or CF₃ CF₂ CF(CF₃)-- or R_(F) 2 and R_(F) 3 takentogether represent --(CF₂)₄ -- or --(CF₂)₅ --, or

(e) one of the structures (a) to (d) in which one or more of thefluorine atoms are replaced by one or more hydrogen or bromine atomsand/or at least two chlorine atoms in a proportion such that at least50% of the atoms bonded to the carbon skeleton of R_(F) are fluorineatoms, and wherein R_(F) contains at least 4 fluorine atoms,

r is 0 or 1;

R² represents R¹, hydrogen or a group OR,

wherein R represents a saturated or unsaturated C₁ -C₂₀ alkyl or C₃ -C₂₀acyl;

and when r is 1, R¹ and R² may exchange their positions; and

each of X and Y independently represent:

hydroxyl;

--OCH₂ CH(OH)CH₂ OH;

--O(CH₂ CH₂ O)_(t) R³,

wherein t is an integer from 1 to 5; and R³ represents a hydrogen atomor C₁ -C₄ alkyl group;

--NR⁴ R⁵ or N⁺ R⁴ R⁵ R⁸,

wherein each of R⁴, R⁵ and R⁸ independently represents a hydrogen atom;a C₁ -C₄ alkyl group, --CH₂ CH₂ O(CH₂ CH₂ O)_(s) R³, wherein srepresents an integer of from 1 to 5, or R⁴ and R⁵ when taken togetherrepresent --(CH₂)_(q) wherein q is an integer of from 2 to 5, or withthe nitrogen atom R⁴ and R₅ form a morpholino group;

--O(CH₂)_(p) Z wherein Z represents a 2-aminoacetic acid group, --NR⁴ R⁵or --N⁺ R⁴ R⁵ R⁸ where R⁸ is as defined for R⁴ and R⁵ above, and p is aninteger of from 1 to 5;

with the proviso that X and Y do not both represent hydroxyl or anionized form derived from hydroxyl.

The compounds of formula (Ia) and (Ib) are described in EP-0478686,which is incorporated herein by reference, and suitable compounds offormula (Ia) and (Ib) and processes for their preparation may readily bedetermined by reference thereto. However, the applicants have found thata particular group of compounds of formula (Ia) are especially preferredfor use in the formulations of the present invention.

Thus, in a further aspect the invention provides a pharmaceuticalaerosol formulation which comprises particulate medicament, afluorocarbon or hydrogen-containing chlorofluorocarbon propellant and asurfactant of general formula (I) ##STR3## wherein n is an integer of 1to 18, especially 2 to 12;

m is an integer of 0 to 17, especially 0 to 11; and

R¹, R² and R³ are each independently a hydrogen atom or a C₁₋₄ alkylgroup.

Particularly preferred compounds of formula (I) are the fluorinatedphosphatidylcholines wherein R¹, R² and R³ each represent methyl, n isan integer of 4 to 8, especially 4 or 6, and m is an integer of 4 to 10,especially 4, 6 or 10.

Certain compounds of formula (I) may contain one or more chiral centres.It will be understood that compounds of formula (I) include all opticalisomers of the compounds of formula (I) and mixtures thereof, includingracemic mixtures thereof.

Contrary to the teaching in the art, the surfactants employed for thepreparation of formulations according to the present invention areeffective stabilisers at low concentrations relative to the amount ofmedicament. Thus, the amount of surfactant employed is desirably in therange of 0.005 to 20% w/w, particularly 0.05 to 20% w/w, moreparticularly 0.05 to 15% w/w, even more particularly about 0.1 to about10% w/w, and preferably 0.5 to about 10% w/w, relative to themedicament.

The particle size of the particulate (e.g. micronised) medicament shouldbe such as to permit inhalation of substantially all of the medicamentinto the lungs upon administration of the aerosol formulation and willthus be less than 100 microns, desirably less than 20 microns, andpreferably in the range 1-10 microns, e.g. 1-5 microns.

The final aerosol formulation desirably contains 0.005-10% w/w,preferably 0.005-5% w/w, especially 0.01-1.0% w/w, of medicamentrelative to the total weight of the formulation.

Medicaments which may be administered in aerosol formulations accordingto the invention include any drug useful in inhalation therapy and whichmay be presented in a form which is substantially completely insolublein the selected propellant. Appropriate medicaments may thus be selectedfrom, for example, analgesics, e.g. codeine, dihydromorphine,ergotamine, fentanyl or morphine; anginal preparations, e.g. diltiazem;antiallergics, e.g. cromoglycate, ketotifen or nedocromil;antiinfectives e.g. cephalosporins, penicillins, streptomycin,sulphonamides, tetracyclines and pentamidine; antihistamines, e.g.methapyrilene; anti-inflammatories, e.g. beclomethasone, flunisolide,budesonide, tipredane, triamcinolone acetonide or fluticasone;antitussives, e.g. noscapine; bronchodilators, e.g. ephedrine,adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol,phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol,salbutamol, salmeterol, terbutaline, isoetharine, tulobuterol,orciprenaline, or (-)-4-amino-3,5-dichloro-α- 6-2-(2-pyridinyl)ethoxy!hexyl!amino!methyl!benzenemethanol; diuretics,e.g. amiloride; anticholinergics e.g. ipratropium, atropine oroxitropium; hormones, e.g. cortisone, hydrocortisone or prednisolone;xanthines e.g. aminophylline, choline theophyllinate, lysinetheophyllinate or theophylline; and therapeutic proteins and peptides,e.g. insulin or glucagon. It will be clear to a person skilled in theart that, where appropriate, the medicaments may be used in the form ofsalts (e.g. as alkali metal or amine salts or as acid addition salts) oras esters (e.g. lower alkyl esters) or as solvates (e.g. hydrates) tooptimise the activity and/or stability of the medicament and/or tominimise the solubility of the medicament in the propellant.

Particularly preferred medicaments for administration using aerosolformulations in accordance with the invention include antiallergics,bronchodilators and antiinflammatory steroids of use in the treatment ofrespiratory disorders such as asthma by inhalation therapy, for examplecromoglycate (e.g. as the sodium salt), salbutamol (e.g. as the freebase or the sulphate salt), salmeterol (e.g. as the xinafoate salt),terbutaline (e.g. as the sulphate salt), reproterol (e.g. as thehydrochloride salt), a beclomethasone ester (e.g. the diproprionate), afluticasone ester (e.g. the propionate) or (-)-4-amino-3,5-dichloro-α-6- 2-(2-pyridinyl)ethoxy!hexyl!amino!methyl!benzenemethanol. Salmeterol,especially salmeterol xinafoate, salbutamol, fluticasone propionate,beclomethasone dipropionate and physiologically acceptable salts andsolvates thereof are especially preferred.

It will be appreciated by those skilled in the art that the aerosolformulations according to the invention may, if desired, contain acombination of two or more active ingredients. Aerosol compositionscontaining two active ingredients (in a conventional propellant system)are known, for example, for the treatment of respiratory disorders suchas asthma. Accordingly the present invention further provides aerosolformulations in accordance with the invention which contain two or moreparticulate medicaments. Thus suitable combinations of bronchodilatoryagents include ephedrine and theophylline, fenoterol and ipratropium,and isoetharine and phenylephrine aerosol formulations.

Preferred aerosol formulations in accordance with the invention comprise(a) an effective amount of a particulate bronchodilatory medicament, (b)an effective amount of a particulate antiinflammatory, preferably asteroidal antiinflammatory medicament, (c) a fluorocarbon orhydrogen-containing chlorofluorocarbon propellant, and (d) a surfactantof general formula (1). Particularly preferred aerosol formulationscontain bronchodilators such as salbutamol (e.g. as the free base or asthe sulphate salt), salmeterol (e.g. as the xinafoate salt) orisoprenaline in combination with an antiinflammatory steroid such as abeclomethasone ester (e.g. the diproprionate) or a fluticasone ester(e.g. the propionate). Alternatively aerosol formulations may contain abronchodilator in combination with an antiallergic such as cromoglycate(e.g. the sodium salt). Combinations of isoprenaline and sodiumcromoglycate, salmeterol and fluticasone propionate, or salbutamol andbeclomethasone dipropionate are especially preferred.

The propellants for use in the invention may be any fluorocarbon orhydrogen-containing chlorofluorocarbon or mixtures thereof having asufficient vapour pressure to render them effective as propellants.Preferably the propellant will be a non-solvent for the medicament.Suitable propellants include, for example, C₁₋₄ hydrogen-containingchlorofluorocarbons such as CH₂ ClF, CClF₂ CHClF, CF₃ CHClF, CHF₂ CClF₂,CHClFCHF₂, CF₃ CH₂ Cl and CClF₂ CH₃ ; C₁₋₄ -hydrogen-containingfluorocarbons such as CHF₂ CHF₂, CF₃ CH₂ F, CHF₂ CH₃ and CF₃ CHFCF₃ ;and perfluorocarbons such as CF₃ CF₃ and CF₃ CF₂ CF₃.

Where mixtures of the fluorocarbons or hydrogen-containingchlorofluorocarbons are employed they may be mixtures of the aboveidentified compounds or mixtures, preferably binary mixtures, with otherfluorocarbons or hydrogen-containing chloro- fluorocarbons for exampleCHClF₂, CH₂ F₂ and CF₃ CH₃. Preferably a single fluorocarbon orhydrogen-containing chlorofluorocarbon is employed as the propellant.Particularly preferred as propellants are C₁₋₄ hydrogen-containingfluorocarbons such as 1,1,1,2-tetrafluoroethane(CF₃ CH₂ F) and1,1,1,2,3,3,3-heptafluoro-n-propane (CF₃ CHFCF₃).

It is desirable that the formulations of the invention contain nocomponents which may provoke the degradation of stratospheric ozone. Inparticular it is desirable that the formulations are substantially freeof chlorofluorocarbons such as CCl₃ F, CCl₂ F₂ and CF₃ CCl₃.

The propellant may additionally contain a volatile adjuvant such as asaturated hydrocarbon for example propane, n-butane, isobutane, pentaneand isopentane or a dialkyl ether for example dimethyl ether. Ingeneral, up to 50% w/w of the propellant may comprise a volatilehydrocarbon, for example 1 to 30% w/w. However, formulations which aresubstantially free of volatile adjuvants are preferred. In certaincases, it may be desirable to include appropriate amounts of water,which can be advantageous in modifying the dielectric properties of thepropellant.

Polar cosolvents which may be incorporated into the formulationsaccording to the present invention include (.e.g C₂₋₆)aliphatic alcoholsand polyols such as ethanol, isopropanol and propylene glycol andmixtures thereof. Preferably ethanol will be employed. In general onlysmall quantities (e.g. 0.05 to 3.0% w/w) of polar cosolvent are requiredto improve the dispersion and the use of quantities in excess of 5% w/wmay disadvantageously tend to dissolve the medicament. Formulationspreferably contain less than 1% w/w, e.g. about 0.1% w/w of polarcosolvent. Polarity may be determined for example, by the methoddescribed in European Patent Application Publication No. 0327777.

In addition to the surfactants of general formula (I), the formulationsaccording to the present invention may optionally contain one or morefurther ingredients conventionally used in the art of pharmaceuticalaerosol formulation. Such optional ingredients include, but are notlimited to, one or more conventional surfactants as hereinafterdescribed and which are physiologically acceptable by inhalation, tastemasking agents, one or more sugars, buffers, antioxidants, water andchemical stabilisers.

Examples of conventional physiologically acceptable surfactants includeoleic acid, sorbitan trioleate (Span ^(R) 85), sorbitan mono-oleate,sorbitan monolaurate, polyoxyethylene (20) sorbitan monolaurate,polyoxyethylene (20) sorbitan monooleate, natural lecithin, oleylpolyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, laurylpolyoxyethylene (4) ether, block copolymers of oxyethylene andoxypropylene, synthetic lecithin, diethylene glycol dioleate,tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glycerylmonooleate, glyceryl monostearate, glyceryl monoricinoleate, cetylalcohol, stearyl alcohol, polyethylene glycol 400, cetyl pyridiniumchloride, benzalkonium chloride, olive oil, glyceryl monolaurate, cornoil, cotton seed oil and sunflower seed oil. Preferred surfactants arelecithin, oleic acid and sorbitan trioleate, for inclusion in apharmaceutical formulation according to the present invention.

Aptly, the aerosol formulations according to the present invention maycontain 0.0001 to 50% w/w, preferably 0.001 to 20, for example 0.001 to1% of sugar relative to the total weight of the formulation. Generallythe ratio of medicament: sugar falls within the range of 1:0.01 to 1:100preferably 1:0.1 to 1:10. Typical sugars which may be used in theformulations include, for example, sucrose, lactose and dextrose,preferably lactose, and reducing sugars such as mannitol and sorbitol,and may be in micronised or milled form.

A particularly preferred embodiment of the invention provides apharmaceutical aerosol formulation consisting essentially of one or moreparticulate medicament, one or more fluorocarbon or hydrogen-containingchlorofluorocarbon propellant and a surfactant of formula (I).

Surfactants according to the present invention can be prepared bytechniques well known in the art, as can be seen for example, byreference to EP-0478686 substantially as hereinbefore described. Asuitable process for preparing surfactants of compounds of formula (I)##STR4## comprises reacting a compound of formula (II) ##STR5## whereinHal represents a halogen atom selected from fluorine, chlorine, bromineand iodine, with

(i) a compound of formula (III) ##STR6## where L is a negatively chargedcounter ion, such as a halide or an alkyl or arylsulphonyloxy group,such as mesylate or tosylate, and

(ii) a hydroxylating agent, such as water.

Suitably the reaction may be carried out in the presence of achlorinated organic solvent, such as chloroform or the like, and a basicmedium, e.g. pyridine or the like.

Compounds of formulae (II) and (III) are well known in the art, and asdescribed above, EP-0478686 is a suitable prior art document which canbe referred to.

The formulations of the invention may be prepared by dispersal of themedicament and surfactant in the selected propellant in an appropriatecontainer, e.g. with the aid of sonication. The process is desirablycarried out under anhydrous conditions to obviate any adverse effects ofmoisture on suspension stability.

The chemical and physical stability and the pharmaceutical acceptabilityof the aerosol formulations according to the invention may be determinedby techniques well known to those skilled in the art. Thus, for example,the chemical stability of the components may be determined by HPLCassay, for example, after prolonged storage of the product. Physicalstability data may be gained from other conventional analyticaltechniques such as, for example, by leak testing, by valve deliveryassay (average shot weights per actuation), by dose reproducibilityassay (active ingredient per actuation) and spray distribution analysis.

The suspension stability of the aerosol formulations according to theinvention is particularly impressive and may be measured by conventionaltechniques, for example by measuring flocculation size distributionusing a back light scattering instrument or by measuring particle sizedistribution by cascade impaction or by the "twin impinger" analyticalprocess. As used herein reference to the "twin impinger" assay means"Determination of the deposition of the emitted dose in pressurisedinhalations using apparatus A" as defined in British Pharmacopaeia 1988,pages A204-207, Appendix XVII C. Such techniques enable the "respirablefraction" of the aerosol formulations to be calculated. As used hereinreference to "respirable fraction" means the amount of active ingredientcollected in the lower impingement chamber per actuation expressed as apercentage of the total amount of active ingredient delivered peractuation using the twin impinger method described above. Theformulations according to the invention have been found to have arespirable fraction of 20% or more by weight of the medicament,preferably 25 to 70%, for example 30 to 60%.

The formulations according to the invention may be filled into canisterssuitable for delivering pharmaceutical aerosol formulations. Canistersgenerally comprise a container capable of withstanding the vapourpressure of the propellant used such as a plastic or plastic-coatedglass bottle or preferably a metal can, for example an aluminium canwhich may optionally be anodised, lacquer-coated and/or plastic-coated,which container is closed with a metering valve. The metering valves aredesigned to deliver a metered amount of the formulation per actuationand incorporate a gasket to prevent leakage of propellant through thevalve. The gasket may comprise any suitable elastomeric material such asfor example low density polyethylene, chlorobutyl, black and whitebutadiene-acrylonitrile rubbers, butyl rubber and neoprene. Suitablevalves are commercially available from manufacturers well known in theaerosol industry, for example, from Valois, France (e.g. DF10, DF30,DF60), Bespak plc, UK (e.g. BK300, BK357) and 3M-Neotechnic Ltd, UK(e.g. Spraymiser™).

Conventional bulk manufacturing methods and machinery well known tothose skilled in the art of pharmaceutical aerosol manufacture may beemployed for the preparation of large scale batches for the commercialproduction of filled canisters. Thus, for example, in one bulkmanufacturing method a metering valve is crimped onto an aluminium canto form an empty canister. The particulate medicament is added to acharge vessel and liquified propellant is pressure filled through thecharge vessel into a manufacturing vessel, together with liquifiedpropellant containing the surfactant. The drug suspension is mixedbefore recirculation to a filling machine and an aliquot of the drugsuspension is then filled through the metering valve into the canister.Typically, in batches prepared for pharmaceutical use, each filledcanister is check-weighed, coded with a batch number and packed into atray for storage before release testing.

Each filled canister is conveniently fitted into a suitable channellingdevice prior to use to form a metered dose inhaler for administration ofthe medicament into the lungs or nasal cavity of a patient. Suitablechannelling devices comprise for example a valve actuator and acylindrical or cone-like passage through which medicament may bedelivered from the filled canister via the metering valve to the nose ormouth of a patient e.g. a mouthpiece actuator. Metered dose inhalers aredesigned to deliver a fixed unit dosage of medicament per actuation or"puff", for example in the range of 10 to 5000 microgram medicament perpuff.

Administration of medicament may be indicated for the treatment of mild,moderate or severe acute or chronic symptoms or for prophylactictreatment. It will be appreciated that the precise dose administeredwill depend on the age and condition of the patient, the particularparticulate medicament used and the frequency of administration and willultimately be at the discretion of the attendant physician. Whencombinations of medicaments are employed the dose of each component ofthe combination will in general be that employed for each component whenused alone. Typically, administration may be one or more times, forexample from 1 to 8 times per day, giving for example 1,2,3 or 4 puffseach time.

Suitable daily doses, may be, for example in the range 50 to 200microgram of salmeterol, 100 to 1000 microgram of salbutamol, 50 to 2000microgram of fluticasone propionate or 100 to 2000 microgram ofbeclomethasone dipropionate, depending on the severity of the disease.

Thus, for example, each valve actuation may deliver 25 microgramsalmeterol, 100 microgram salbutamol, 25, 50, 125 or 250 microgramfluticasone propionate or 50, 100, 200 or 250 microgram beclomethasonedipropionate. Typically each filled canister for use in a metered doseinhaler contains 100, 160 or 240 metered doses or puffs of medicament.

The filled canisters and metered dose inhalers described herein comprisefurther aspects of the present invention.

A still further aspect of the present invention comprises a method oftreating respiratory disorders such as, for example, asthma, whichcomprises administration by inhalation of an effective amount of aformulation as herein described.

The following non-limitative Examples serve to illustrate the invention.

EXAMPLE 1 Example 1a

A compound of formula (I) (R¹, R², R³ ═CH₃, n=6, m=6)

To a dry 1 L four neck round bottom flask fitted with mechanicalstirring, a temperature probe and nitrogen inlet, was added 150 mL (5volumes) of dry isopropyl ether (stabilised with BHT). The solution wascooled to -25° C. and then 3.08 mL (5.07 g, 33.07 mmol) of POCl₃ wasadded, followed by 5.53 mL (4.02 g, 39.68 mmol) of triethylamine. Thehazy solution was stirred for 5 minutes before the addition of 30.00 g(31.50 mmol) of8,8,9,9,10,10,11,11,12,12,13,13,13-tridecafluoro-tridecanoic acid3-hydroxy-2-(8,8,9,9,10,10,11,11,12,12,13,13,13-tridecafluorotridecanoyloxy)-propylester¹in 75 mL (2.5 vol) of isopropyl ether over a 20 minute time period,being sure to keep the internal temperature between -26° and -23° C. Themixture was allowed to warm up to 20° C. over the course of 1 hour, andwashed with 2×40 mL (2.5 vol) of isopropyl ether, and then the filtratewas evaporated to a volume of about 100 mL at 25° C. CHCl₃ (ethanol free500 mL) was added and the solution was evaporated at 25° C. to a volumeof about 100 mL.

¹. Prepared according to EP-0478686.

120 mL (8.3 vol) of ethanol free chloroform was added. The solution wascooled to 0° C. and then 12.8 mL (12.3 g, 155.6 mmol) of pyridine and9.56 g (34.7 mmol) of choline tosylate were added. The reaction mixturewas allowed to warm up to 25° C. over the course of 1 hour and thenstirred for 7 hours at ambient temperature. Water 2.8 mL (155.6 mmol)was added and the mixture was stirred at 25° C. for 5 hours. The mixturewas stored overnight at 0° C., and then 250 mL of absolute ethanol wasadded.

TMD-8 ion exchange resin (400 g) was placed in a 600 mL filter funnel.The resin was washed with absolute ethanol (3×250 mL). The procedureyielded about 300 g of resin after pulling a vacuum for an additional 15minutes. The TMD-8 ion exchange resin (300 g) was added and thesuspension was stirred for 2 hours at 25° C. The resin was filtered, andthe cake was washed with 3×250 mL of absolute ethanol. The filtrate wasstored overnight at 0° C., and then the solvent was evaporated at atemperature of 25°-30° C. to a total volume of 200 mL. 500 mL toluenewas added, and the solvent was evaporated at 50° C. to a volume of about400 mL at which time the product began to gel out of solution. 500 mLtoluene was added and the solvent was evaporated to a total volume of500 mL. The suspension was stirred vigorously for 12 hours at ambienttemperature and the solid powder was collected by filtration. The cakewas washed with 2×200 mL of toluene to afford 23.0 g (65.4%) of thetitle compound.

Example 1b

A compound of formula (I) (R¹, R², R³ ═CH₃, n=4, m=10)

To a dry 2 L four neck round bottom flask fitted with mechanicalstirring, temperature probe, nitrogen inlet and septum, was added 100 mldiethylether. The solution was cooled to -20° C., and then 6.7 mL ofPOCl₃ was added, followed by 12.1 mL of triethylamine. 62.5 gm of12,12,13,13,14,14,15,15,15-Nonafluoropentadecanoic acid1-hydroxymethyl-2-(12,12,13,13,14,14,15,15,15-nonafluoropentadecanoyloxy)-ethylester¹ was dissolved in 500 mL diethylether, chilled in an ice bath, andthen added over a 30 minute time period to the POCl₃ solution. Themixture was allowed to warm to room temperature.

¹. Prepared according to EP-0478686.

The mixture was filtered, and washed with 3×100 mL diethylether, and thesolvent removed under high vacuum. 100 mL chloroform was added todissolve the residue, followed by 200 mL acetonitrile, 29.2 mL pyridineand 10.1 gm of choline chloride. The mixture was allowed to warm to roomtemperature, and then stirred under a nitrogen atmosphere overnight. 6.5mL of water was then added, and the reaction was stirred at roomtemperature over 21/2 hours.

The solvent was removed on rotary evaporation, and the resulting oilpumped under high vacuum for approximately 1 hour.

Meanwhile, 850 g of ion exchange resin (TMD-8) was treated with 2×1 Lchloroform/methanol (4:1) mixture, 2×1 L methanol and 1×1 Lchloroform/methanol (4:1).

The compound was diluted in 1,500 mL chloroform, and the ion exchangeresin was added, followed by stirring at room temperature for 2 hours.The solvent was then removed, the resultant filtrate rotary evaporatedto an oil, and placed in the freezer overnight, and further purified toyield 27.58 gm of the title compound.

Other surfactants of formula (I) described in the Examples hereinafterwere prepared by analogous methods.

EXAMPLE 2

Micronised salbutamol base (26 mg) and compound of formula (I) (R¹,R²,R³═CH₃, n=4, m=10) (5.1 mg) were weighed into a 15 ml transparent glassaerosol vial and a metering valve was crimped into place.1,1,1,2-Tetrafluoroethane (P134a, 18.2 g) and heptafluoropropane (P227,21 g) were added to the vial through the valve. The vial was sonicatedfor 30 sec. to disperse the drug and surfactant.

EXAMPLES 3-6

Using the procedure described in Example 2 the following formulationswere prepared:

    ______________________________________                                        Example Drug            Propellant                                                                              Surfactant/mg                               ______________________________________                                        3       Salbutamol base (26mg)                                                                        P227      1.2                                         4       Salbutamol base (26mg)                                                                        P227      11                                          5       Salbutamol sulphate (32mg)                                                                    P227      3.1                                         6       Salbutamol sulphate (32mg)                                                                    P134a     0.5                                         ______________________________________                                    

EXAMPLES 7 to 20

The aerosol formulations of Examples 7 to 20 were prepared in largescale batches. A metering valve (e.g. DF60 valve) was crimped into an 8ml aluminium can (12.5 ml can in the case of Examples 19 and 20) and thecan was purged with 1,1,1,2-tetrafluoroethane prior to filling. Theparticulate medicament (micronised) was added to a charge vessel andliquified 1,1,1,2-tetrafluoroethane propellant was pressure filledthrough the charge vessel into a manufacturing vessel, together withliquified propellant containing the surfactant of formula (I) (R¹, R²and R³ ═CH₃, n and m as indicated). The drug suspension was mixed beforerecirculation to a filling machine and an aliquot (typically 12 g) ofthe drug suspension was then filled through the metering valve into thecanister to provide an inhaler typically containing an equivalent of 160actuations of 75 mg (designed to deliver 120 actuations). The followinginhalers were prepared:

    ______________________________________                                                        Per 75.0mg Per 160 actuations                                 Example 7       actuation  (i.e. per can)                                     ______________________________________                                        Fluticasone propionate                                                                        275μg   44mg                                               Surfactant (n = 4, m = 4)                                                                     27.5μg  4.4mg                                              1,1,2-Tetrafluoroethane                                                                       to 75.0mg  to 12.0g                                           ______________________________________                                    

    ______________________________________                                                        Per 75.0mg Per 160 actuations                                 Example 8       actuation  (i.e. per can)                                     ______________________________________                                        Fluticasone propionate                                                                        275μg   44mg                                               Surfactant (n = 4, m = 4)                                                                     2.75μg  0.44mg                                             1,1,1,2-Tetrafluoroethane                                                                     to 75.0mg  to 12.0g                                           ______________________________________                                    

    ______________________________________                                                        Per 75.0mg Per 160 actuations                                 Example 9       actuation  (i.e. per can)                                     ______________________________________                                        Fluticasone propionate                                                                        275μg   44mg                                               Surfactant (n = 6, m = 6)                                                                     27.5μg  4.4mg                                              1,1,1,2-Tetrafluoroethane                                                                     to 75.0mg  to 12.0g                                           ______________________________________                                    

    ______________________________________                                                        Per 75.0mg Per 160 actuations                                 Example 10      actuation  (i.e. per can)                                     ______________________________________                                        Fluticasone propionate                                                                        275μg   44mg                                               Surfactant (n = 6, m = 6)                                                                     2.75μg  0.44mg                                             1,1,1,2-Tetrafluoroethane                                                                     to 75.0mg  to 12.0g                                           ______________________________________                                    

    ______________________________________                                                        Per 75.0mg Per 160 actuations                                 Example 11      actuation  (i.e. per can)                                     ______________________________________                                        Fluticasone propionate                                                                        27.5μg  4.4mg                                              Surfactant (n = 4, m = 4)                                                                     2.75μg  0.44mg                                             1,1,1,2-Tetrafluoroethane                                                                     to 75.0mg  to 12.0g                                           ______________________________________                                    

    ______________________________________                                                        Per 75.0mg Per 160 actuations                                 Example 12      actuation  (i.e. per can)                                     ______________________________________                                        Fluticasone propionate                                                                        27.5μg  44mg                                               Surfactant (n = 4, m = 4)                                                                     0.275μg 0.044mg                                            1,1,1,2-Tetrafluoroethane                                                                     to 75.0mg  to 12.0g                                           ______________________________________                                    

    ______________________________________                                                        Per 75.0mg Per 160 actuations                                 Example 13      actuation  (i.e. per can)                                     ______________________________________                                        Fluticasone propionate                                                                        27.5μg  4.4mg                                              Surfactant (n = 6, m = 6)                                                                     2.75μg  0.44mg                                             1,1,1,2-Tetrafluoroethane                                                                     to 75.0mg  to 12.0g                                           ______________________________________                                    

    ______________________________________                                                        Per 75.0mg Per 160 actuations                                 Example 14      actuation  (i.e. per can)                                     ______________________________________                                        Fluticasone propionate                                                                        27.5μg  4.4mg                                              Surfactant (n = 6, m = 6)                                                                     0.275μg 0.044mg                                            1,1,1,2-Tetrafluoroethane                                                                     to 75.0mg  to 12.0g                                           ______________________________________                                    

    ______________________________________                                                        Per 75.0mg Per 160 actuations                                 Example 15      actuation  (i.e. per can)                                     ______________________________________                                        Salmeterol xinafoate                                                                          39.88μg 6.38mg                                             Surfactant (n = 4, m = 4)                                                                     3.99μg  0.64mg                                             1,1,1,2-Tetrafluoroethane                                                                     to 75.0mg  to 12.0g                                           ______________________________________                                    

    ______________________________________                                                        Per 75.0mg Per 160 actuations                                 Example 16      actuation  (i.e. per can)                                     ______________________________________                                        Salmeterol xinafoate                                                                          39.88μg 6.38mg                                             Surfactant (n = 4, m = 4)                                                                     0.399μg 0.064mg                                            1,1,1,2-Tetrafluoroethane                                                                     to 75.0mg  to 12.0g                                           ______________________________________                                    

    ______________________________________                                                        Per 75.0mg Per 160 actuations                                 Example 17      actuation  (i.e. per can)                                     ______________________________________                                        Salmeterol xinafoate                                                                          39.88μg 6.38mg                                             Surfactant (n = 6, m = 6)                                                                     3.99μg  0.64mg                                             1,1,1,2-Tetrafluoroethane                                                                     to 75.0mg  to 12.0g                                           ______________________________________                                    

    ______________________________________                                                        Per 75.0mg Per 160 actuations                                 Example 18      actuation  (i.e. per can)                                     ______________________________________                                        Salmeterol xinafoate                                                                          39.88μg 6.38mg                                             Surfactant (n = 6, m = 6)                                                                     0.399μg 0.064mg                                            1,1,1,2-Tetrafluoroethane                                                                     to 75.0mg  to 12.0g                                           ______________________________________                                    

    ______________________________________                                                                     Per 248                                                            Per 75.0mg actuations (i.e.                                 Example 19        actuation  per can)                                         ______________________________________                                        Beclomethasone dipropionate hydrate                                                             54.32μg 13.47mg                                          Surfactant (n = 6, m = 6)                                                                       5.4μg   1.35mg                                           Purified water B.P.                                                                             0.045mg    11.16mg                                          1,1,1,2-Tetrafluoroethane                                                                       to 75.0mg  to 18.6g                                         ______________________________________                                    

Inhaler contains equivalent of 248 actuations (delivers 200 actuations).

    ______________________________________                                                                     Per 248                                                            Per 75.0mg actuations (i.e.                                 Example 20        actuation  per can)                                         ______________________________________                                        Beclomethasone dipropionate hydrate                                                             54.32μg 13.47mg                                          Surfactant (n = 4, m = 4)                                                                       5.4μg   1.35mg                                           Purified water B.P.                                                                             0.045mg    11.16mg                                          1,1,1,2-Tetrafluoroethane                                                                       to 75.0mg  to 18.6g                                         ______________________________________                                    

Inhaler contains equivalent of 248 actuations (delivers 200 actuations).

EXAMPLES 21 to 31

Micronized drug and surfactant were weighed into 15 ml transparentaerosol vials (Wheaton Industries, NJ). A metering valve (Bespak valveNo. BK300, or Valois DF60 MK VI) was crimped onto each vial. Finally,1,1,1,2-tetrafluoroethane (P134a) or 1,1,1,2,3,3,3-heptafluoro-n-propane(P227) was added to the vial through the valve. Vials were thensonicated for 30 seconds.

    ______________________________________                                                                             Propellant                                                                    P134a (18g)                                                  Surfactant                                                                              Surfactant                                                                           or P227                                  Example                                                                              Drug (amount)                                                                              type      mg/inhaler                                                                           (22g)                                    ______________________________________                                        21     Salbutamol Base                                                                            n = 8,m = 4                                                                             2.0    P134a                                           (26mg)                                                                 22     Salbutamol Base                                                                            n = 6,m = 10                                                                            1.8    P134a                                           (26mg)                                                                 23     Salbutamol Sulphate                                                                        n = 6,m = 10                                                                            2.3    P134a                                           (29mg)                                                                 24     Salbutamol Base                                                                            n = 4,m = 10                                                                            1.2    P227                                            (26mg)                                                                 25     Salbutamol Base                                                                            n = 8,m = 4                                                                             2.0    P227                                            (26mg)                                                                 26     Salbutamol Base                                                                            n = 6,m = 10                                                                            2.8    P227                                            (26mg)                                                                 27     Salbutamol Sulphate                                                                        n = 8,m = 4                                                                             2.0    P227                                            (26mg)                                                                 28     Salbutamol Sulphate                                                                        n = 6,m = 10                                                                            2.0    P227                                            (26mg)                                                                 29     Salbutamol Sulphate                                                                        n = 4,m = 10                                                                            3.1    P227                                            (26mg)                                                                 30     Salmeterol (9mg)                                                                           n = 8,m = 4                                                                             2.5    P227                                     31     Salmeterol (9mg)                                                                           n = 6,m = 10                                                                            3.0    P227                                     ______________________________________                                    

EXAMPLES 32 to 43

Stock solutions of surfactants with concentration of 0.33 mg/g wereprepared in glass according to the following procedure. 6 mg ofsurfactant were weighed into the safety coated glass vials. A DF60 MKIVvalve was crimped onto the vial using a Pamasol crimper. 18.2 grams of1,1,1,2-tetrafluoroethane (P134a) were filled through the valve using aPamasol pressure filler. Then, the inhalers were sonicated for 30 sec todisperse surfactants.

Appropriate amount surfactant or surfactant stock solution was deliveredinto the safety coated glass vials before a drug was added into thesevials. A DF60 MKIV valve was crimped onto the canister, and P134apropellant as received was filled through the valve. After filling wascomplete, the inhalers were sonicated for 30 sec to disperse the drugand surfactant.

    ______________________________________                                                                 Surfactant                                                                              Surfactant                                 Example Drug (amount)    type      mg/inhaler                                 ______________________________________                                        32      Salbutamol Sulphate (29 mg)                                                                    n = 4,m = 10                                                                            1.0                                        33      Salbutamol Sulphate (29 mg)                                                                    n = 4,m = 4                                                                             1.0                                        34      Salbutamol Sulphate (29 mg)                                                                    n = 6,m = 6                                                                             1.0                                        35      Salbutamol Sulphate (29 mg)                                                                    n = 8,m = 4                                                                             1.0                                        36      Salmeterol (8 mg)                                                                              n = 4,m = 10                                                                            0.1                                        37      Salmeterol (8 mg)                                                                              n = 4,m = 4                                                                             0.1                                        38      Salmeterol (8 mg)                                                                              n = 6,m = 6                                                                             0.1                                        39      Salmeterol (8 mg)                                                                              n = 8,m = 4                                                                             0.1                                        40      Fluticasone Propionate(6mg)                                                                    n = 4,m = 10                                                                            1.0                                        41      Fluticasone Propionate(6mg)                                                                    n = 4,m = 4                                                                             1.0                                        42      Fluticasone Propionate(6mg)                                                                    n = 6,m = 6                                                                             1.0                                        43      Fluticasone Propionate(6mg)                                                                    n = 8,m = 4                                                                             1.0                                        ______________________________________                                    

EXAMPLES 44 to 51

Examples 44 to 51 were prepared as described for Examples 32 to 43 butusing 1,1,1,2-tetrafluoroethane (P134a) containing 600 ppm of water. Wetpropellant was made by mixing water and the propellant in a cylinder,and then shaking over night.

    ______________________________________                                                                 Surfactant                                                                              Surfactant                                 Example Drug (amount)    type      mg/inhaler                                 ______________________________________                                        44      BDP hydrate (12 mg)                                                                            n = 4,m = 10                                                                            1.0                                        45      BDP hydrate (12 mg)                                                                            n = 4,m = 4                                                                             1.0                                        46      BDP hydrate (12 mg)                                                                            n = 6,m = 6                                                                             1.0                                        47      BDP hydrate (12 mg)                                                                            n = 8,m = 4                                                                             1.0                                        48      Salbutamol Sulphate (29 mg)                                                                    n = 4,m = 10                                                                            1.0                                        49      Salbutamol Sulphate (29 mg)                                                                    n = 4,m = 4                                                                             1.0                                        50      Salbutamol Sulphate (29 mg)                                                                    n = 6,m = 6                                                                             1.0                                        51      Salbutamol Sulphate (29 mg)                                                                    n = 8,m = 4                                                                             1.0                                        ______________________________________                                    

In the Examples 32 to 51, a range of drug/surfactant ratios (0.2% to15%) was tested for each compound and each drug. The suspensionstability was examined using a back light scattering technique. Thesuspension stability can be improved at surfactant concentration as lowas 0.2% of drug weight. Drug deposition on the walls of the glass vialswas also examined and reduced with increases in surfactantconcentration. Drug/surfactant ratio as low as 0.1% was able to reducedrug deposition on the glass wall significantly, even at high watercontent in propellant, demonstrated in Examples 44 to 50.

EXAMPLES 52 to 67

Examples 52 to 67 were prepared as described for Examples 32 to 43 butusing aluminium canisters rather than glass vials and 18.2 g1,1,1,2-tetrafluoroethane (P134a). In Examples 64 to 67 wet P134acontaining 350 ppm of water (prepared as described in Examples 44 to 51)was used.

    ______________________________________                                                                 Surfactant                                                                              Surfactant                                 Example Drug (amount)    type      mg/inhaler                                 ______________________________________                                        52      Salbutamol Sulphate (29 mg)                                                                    n = 4,m = 10                                                                            1.0                                        53      Salbutamol Sulphate (29 mg)                                                                    n = 4,m = 4                                                                             1.0                                        54      Salbutamol Sulphate (29 mg)                                                                    n = 6,m = 6                                                                             1.0                                        55      Salbutamol Sulphate (29 mg)                                                                    n = 8,m = 64                                                                            1.0                                        56      Salmeterol (8 mg)                                                                              n = 4,m = 10                                                                            1.0                                        57      Salmeterol (8 mg)                                                                              n = 4,m = 4                                                                             1.0                                        58      Salmeterol (8 mg)                                                                              n = 6,m = 6                                                                             1.0                                        59      Salmeterol (8 mg)                                                                              n = 8,m = 4                                                                             1.0                                        60      Fluticasone Propionate(6mg)                                                                    n = 4,m = 10                                                                            1.0                                        61      Fluticasone Propionate(6mg)                                                                    n = 4,m = 4                                                                             1.0                                        62      Fluticasone Propionate(6mg)                                                                    n = 6,m = 6                                                                             1.0                                        63      Fluticasone Propionate(6mg)                                                                    n = 8,m = 4                                                                             1.0                                        64      BDP hydrate (12 mg)                                                                            n = 4,m = 10                                                                            1.0                                        65      BDP hydrate (12 mg)                                                                            n = 4,m = 4                                                                             1.0                                        66      BDP hydrate (12 mg)                                                                            n = 8,m = 4                                                                             1.0                                        67      BDP hydrate (12 mg)                                                                            n = 6,m = 6                                                                             1.0                                        ______________________________________                                    

EXAMPLES 68 to 73

Examples 68 to 73 were prepared as described for Examples 21 to 31, thesurfactant employed in each Example 68 to 73 being n=4, m=10.

    ______________________________________                                                       Surfactant    Propellant                                       Example 68     (amount)      (amount)                                         ______________________________________                                        Salmeterol xinafoate (14mg)                                                                  n = 4,m = 10 (3.9mg)                                                                        P134a (18.05mg)                                  ______________________________________                                    

    ______________________________________                                                     Surfactant     Propellant                                        Example 69   (amount        (amount)                                          ______________________________________                                        Amiloride HCl (32.3mg)                                                                     n = 4, m = 10 (1.7mg)                                                                        P134a (18.0mg)                                    ______________________________________                                    

    ______________________________________                                        Example 70                                                                    ______________________________________                                        Salmeterol xinafoate (9.9mg)                                                                 n = 4, m = 10 (2.2mg)                                                                       P227 (20.8mg)                                    ______________________________________                                    

    ______________________________________                                        Example 71                                                                    ______________________________________                                        Fluticasone propionate (26.7mg)                                                               n = 4, m = 10 (3.0mg)                                                                       P227 (20.7mg)                                   ______________________________________                                    

    ______________________________________                                        Example 72                                                                    ______________________________________                                        Beclomethasone dipropionate                                                                  n = 4, m = 10 (2.2mg)                                                                       P227 (20.7mg)                                    (26.9mg)                                                                      ______________________________________                                    

    ______________________________________                                        Example 73                                                                    ______________________________________                                        Amiloride HCl (30.7mg)                                                                     n = 4, m = 10 (2.0mg)                                                                        P227 (20.7mg)                                     ______________________________________                                    

We claim:
 1. A pharmaceutical aerosol formulation which comprisesparticulate medicament, a fluorocarbon or hydrogen-containingchlorofluorocarbon propellant and a surfactant, which is soluble in saidpropellant, of general formula (Ia) or (Ib) ##STR7## wherein: R¹represents:R_(F) (CH₂)_(a) --(CH═CH)_(b) --(CH₂)_(c) --(CH═CH)_(d)--(CH₂)_(e) --A--; R_(F) --(CH₂)_(f) --OCH₂ CH(CH₂ OH)CH₂ --A--; R_(F)--(CH₂)_(g) --OCH₂ CH(CH₂ OH)--A--; wherein --A-- represents --O--,--C(O)O--, --R⁶ (R⁷)N⁺ --, (wherein each of R⁶ and R⁷ represents C₁ -C₄alkyl or hydroxyethyl), --(CH₂)_(t) --, wherein t=0 or 1 or--C(O)N(R⁹)--(CH₂)_(q) --B, wherein q is an integer from 0 to 12, Brepresents --O-- or --C(O)--, and R⁹ is hydrogen or R⁶, and wherein thesum of a+c+e is from 0 to 17, the sum b+d is from 0 to 12 and each of fand g is from 1 to 12;R_(F) --(CH₂ --CH₂ --O)_(h) --; R_(F)--(CH(CH₃)CH₂ O)_(h) --; R_(F) --(--CH₂ --CH₂ --S)_(h) --, wherein h isfrom 1 to 12; and wherein R_(F) represents a fluorine-containing moietyhaving one of the following structures:(a) F(CF₂)_(i) --, wherein i isfrom 1 to 18, (b) (CF₃)₂ CF(CF₂)_(j) --, wherein j is from 0 to 8, (c)R_(F) 1(CF₂ CF(CF₃))_(k) --, wherein k is from 1 to 4, and R_(F) 1represents CF₃ --, C₂ F₅ -- or (CF₃)₂ CF--, (d) R_(F) 2(R_(F) 3)CFO(CF₂CF₂)_(l) wherein l is from 1 to 6 and wherein each of R_(F) 2 and R_(F)3 independently represents CF₃ --, C₂ F₅ --, n-C₃ F₇ -- or CF₃ CF₂CF(CF₃)-- or R_(F) 2 and R_(F) 3 taken together represent --(CF₂)₄ -- or--(CF₂)₅ --, or (e) one of the structures (a) to (d) in which one ormore of the fluorine atoms are replaced by one or more hydrogen orbromine atoms and/or at least two chlorine atoms in a proportion suchthat at least 50% of the atoms bonded to the carbon skeleton of R_(F)are fluorine atoms, and wherein R_(F) contains at least 4 fluorineatoms, r is 0 or 1; R² represents R¹, hydrogen or a group OR, wherein Rrepresents a saturated or unsaturated C₁ -C₂₀ alkyl or C₃ -C₂₀ acyl; andwhen r is 1, R¹ and R² may exchange their positions; and each of X and Yindependently represent:hydroxyl; --OCH₂ CH(OH)CH₂ OH; --O(CH₂ CH₂O)_(t) R³, wherein t is an integer from 1 to 5; and R³ represents ahydrogen atom or C₁ -C₄ alkyl group;--NR⁴ R⁵ or N⁺ R⁴ R⁵ R⁸, whereineach of R⁴, R⁵ and R⁸ independently represents a hydrogen atom; a C₁ -C₄alkyl group, --CH₂ CH₂ O(CH₂ CH₂ O)_(s) R³, wherein s represents aninteger of from 1 to 5, or R⁴ and R⁵ when taken together represent--(CH₂)_(q) wherein q is an integer of from 2 to 5, or with the nitrogenatom R⁴ and R⁵ form a morpholino group; --O(CH₂)_(p) Z wherein Zrepresents a 2-aminoacetic acid group, --NR⁴ R⁵ or --N⁺ R⁴ R⁵ R⁸ whereR⁸ is as defined for R⁴ and R⁵ above, and p is an integer of from 1 to5; with the proviso that X and Y do not both represent hydroxyl or anionized form derived from hydroxyl.
 2. A pharmaceutical aerosolformulation which comprises particulate medicament, a fluorocarbon orhydrogen-containing chlorofluorocarbon propellant and a surfactant,which is soluble in said propellant, of general formula (I) ##STR8##wherein n is an integer of 1 to 18;m is an integer of 0 to 17; and R¹,R² and R³ are each independently a hydrogen atom or a C₁₋₄ alkyl group.3. A formulation according to claim 2, wherein R¹, R² and R³ eachrepresent methyl.
 4. A formulation according to claim 2, wherein n is aninteger of 4 to
 8. 5. A formulation according to claim 4, wherein n is 4or
 6. 6. A formulation according to any of claim 2, wherein m is aninteger of 4 to
 10. 7. A formulation according to claim 6, wherein m is4, 6 or
 10. 8. A formulation according to claim 1, wherein thesurfactant is present in an amount of 0.05 to 15% w/w, relative tomedicament.
 9. A formulation according to claim 8, wherein thesurfactant is present in an amount of 0.5 to 10% w/w, relative tomedicament.
 10. A formulation according to claim 1, wherein theparticulate size of medicament is in the range of 1-10 microns.
 11. Aformulation according to claim 1, wherein medicament is present in anamount of 0.01-1.0% w/w, relative to the total weight of theformulation.
 12. A formulation according to claim 1, wherein particulatemedicament is selected from the group consisting of cromoglycate,salbutamol, salmeterol, terbutaline, reproterol, a beclomethasone ester,a fluticasone ester and (-)-4-amino-3,5-dichloro-α- 6-2-(2-pyridinyl)ethoxy!hexyl!amino!methyl!benzenemethanol.
 13. Aformulation according to claim 12, wherein particulate medicament isselected from the group consisting of salmeterol xinafoate, salbutamol,fluticasone propionate, beclomethasone dipropionate and physiologicallyacceptable salts and solvates thereof.
 14. A formulation according toclaim 2, which comprises (a) an effective amount of a particulatebronchodilatory medicament, (b) an effective amount of a particulateantiinflammatory, (c) a fluorocarbon or hydrogen-containingchlorofluorocarbon propellant, and (d) a surfactant of general formula(I).
 15. A formulation according to claim 1, wherein said propellant isC₁₋₄ hydrogen-containing fluorocarbon.
 16. A formulation according toclaim 15, wherein said propellant is selected from1,1,1,2-tetrafluoroethane(CF₃ CH₂ F) and1,1,1,2,3,3,3-heptafluoro-n-propane (CF₃ CHFCF₃).
 17. A formulationaccording to claim 2, which consists essentially of one or moreparticulate medicament, one or more fluorocarbon or hydrogen-containingchlorofluorocarbon propellant and a surfactant of formula (I).
 18. Amethod of treating respiratory disorders in a human patient, whichcomprises administration by inhalation of an effective amount of aformulation according to claim
 1. 19. A process of preparing aformulation according to claim 1, which comprises dispersal of saidmedicament and surfactant in said propellant.